Project Summary Vitamin A and its active metabolite, retinoic acid (RA), are known to exert both pro-inflammatory and anti-inflammatory functions depending on different contexts. RA can suppress inflammation and induce tolerance under steady state. Paradoxically, it can also act as an adjuvant to promote ongoing inflammation against infections. This conundrum on the functions of RA is much less understood for autoimmunity. Evidence is lacking on whether and how RA affects the initiation and progression of autoimmune disorders, which as a whole are a leading cause of death and disability in the United States. In the proposed research, we aim to define the complex roles of RA in autoimmunity. Based on the literature and our preliminary results, we hypothesize that the effects of RA on autoimmune responses are dependent on the stage of disease and that RA suppresses the initiation of autoimmunity but promotes its progression. Using systemic lupus erythematosus (lupus) as our disease model of autoimmunity, we plan to achieve two aims to test this hypothesis. Aim 1 is to determine whether RA suppresses inflammation to prevent the initiation of lupus and delineate a molecular mechanism of action. As our preliminary results have shown that RA exacerbates lupus that is already initiated, Aim 2 is to determine the mechanism by which RA promotes inflammation in the continuation phase of autoimmune lupus. Successful completion of this study will elucidate the complex roles of RA in autoimmunity and provide much needed information concerning the use of, or avoidance of, vitamin A supplementation in lupus patients. Such information may help decrease the occurrence and/or severity of inflammatory flares suffered by these patients.